Process for synthesizing d-tocotrienols

ABSTRACT

A process of forming a d-tocotrienols from a (2S) 2-hydroxymethyl-6-hydroxy-alkylchroman compound, through reaction with a farnesyl Grignard or sulfone compound. Various methods of making the (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound are disclosed.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser. No. 60/510,196 filed Oct. 10, 2003.

FIELD OF THE-INVENTION

This invention relates generally to processes for producing certain compounds in the Vitamin E family, also known generally as tocols. In particular, the invention relates to processes for producing tocotrienols having the structure and absolute configuration the same as found in nature.

BACKGROUND OF THE INVENTION

There are four naturally occurring tocotrienols, d-alpha-, d-beta-, d-gamma-, and d-delta-tocotrienol. The four naturally occurring tocotrienols have the (R) absolute configuration at the C-2 chroman ring position, and the chemical structures wherein R₁ (at C-5 chroman ring position), R₂ (at C-7 chroman ring position), and R₃ (at C-8 chroman ring position) are methyl in the d-alpha-homologue, R₁ and R₃ are methyl in the d-beta-homologue, R₂ and R₃ are methyl in the d-gamma-homologue, and R₃ is methyl in the d-delta homologue, with the non-methyl R groups being hydrogen atoms.

The chroman ring numbering system referenced above is used herein for continuity. As shown, each of the four naturally occurring d-tocotrienols has an (R) absolute configuration at the chiral 2-position carbon of the chroman ring. Further, the tocotrienols have a trans double bond site at each of the 3′ and 7′ chain positions in the 16-carbon side chain attached to the chroman ring. The geometry of each of these double bond sites is trans (also referred to as E) in all four natural tocotrienols. For a general discussion of the natural tocotrienols, see L. Machlin, ed., “Vitamin E: A Comprehensive Treatise”, Dekker, New York, 1980, pp. 8-65.

The family of d-tocotrienols has been shown to possess a wide variety of health benefits. For a discussion of the health-promoting benefits of tocotrienols, see T. R. Watkins, et al., “Tocotrienols: Biological and Health Effects”, K. L. Jordan Heart Foundation, Montclair, N.J., 1999; C. Chenevert and G. Courchesne, “Synthesis of (S)-alpha-Tocotrienol via an enzymatic desymmetrization of an achiral chroman derivative”, Tetrahedron Letters 43, 7971-7973 (2002); and B. C. Pearce et al., “Hypocholesterolemic Activity of Synthetic and Natural Tocotrienols”, J. Med. Chem. 35, 3595-3606 (1992).

d-Tocotrienols are present in the oils, seeds, and other parts of many plants used as foods (see pp. 99-165 in L. Machlin, ed., “Vitamin E: A Comprehensive Treatise” for a discussion of the occurrence of tocotrienols in foods). However, since d-tocotrienol levels are very low in these natural sources it is often necessary to supplement the typical human diet with additional tocotrienols in order to realize the potential health advantages provided by these compounds. Tocotrienol-containing concentrates can be prepared from certain plant oils and plant oil by-products such as rice bran oil or palm oil deodorizer distillate. For examples of such isolation processes, see for instance A. G. Top et al., U.S. Pat. No. 5,190,618 (1993) or Y. Tanaka and T. Ichitani, Jpn. Kokai Tokkyo Koho appl. JP 2002-168227 20020610 (2003), CAN 139:52035. There are two problems inherent in obtaining d-tocotrienols from natural sources. Firstly, there is only a limited and inadequate supply of the requisite plant or seed oils available for use as tocotrienol feedstocks. Secondly, the d-tocotrienol yield from such processes is a mixture of varying amounts of all of the natural tocols. In order to obtain a pure member of the d-tocotrienol family, it has been necessary to resort to very expensive procedures such as preparative scale reversed-phase chromatography or simulated moving bed chromatography. For an example of such a purification process, see M. Kitano et al., Japanese Patent No. 200302777 (2003), CAN 133:309299.

In view of the limited availability and difficulty of isolation of natural d-tocotrienols, it is necessary to seek ways for obtaining the materials through chemical synthesis from commercially available raw materials. The synthesis of tocotrienols in the natural d-form, having the (2R) chiral configuration and trans double bonding at the proper locations in the side chain, has heretofore proven to be of considerable difficulty.

The first attempt to synthesize a member of the tocotrienol family was reported by P. Karrer and H. Rentschler (Helv. Chim. Acta 27, 1297-1300 (1944)); these workers failed to synthesize tocotrienols. Karrer and Rentschler obtained compounds having cyclization of the side chain. A later attempt by D. McHale et al. (J. Chem. Soc. 1963, 784-791) likewise failed due to inadvertant cyclization of the olefin-containing side chain.

Syntheses of various members of the tocotrienol family in the d,l- or (RS)-form have been published. Schudel et al. (Helv. Chim. Acta 46, 2517-2526 (1963)) completed a synthesis of alpha- and delta-tocotrienols in racemic form (dl-alpha- and delta-tocotrienols, each having a 50/50 mixture of R- and S-enantiomers at the 2-position). Schudel's synthesis was not amenable to synthesis of the natural 2R-isomer. Other tocotrienol syntheses include the works reported by H. Mayer et al., Helv. Chim. Acta 50, 1376-11393 (1967); H.-J. Kabbe and H. Heitzer, Synthesis 1978, 888-889; M. Kajiwara et al., Heterocycles 14, 1995-1998 (1980); S. Urano et al., Chem. Pharm. Bull. 31, 4341-4345 (1983), Pearce et al., J. Med. Chem. 35, 3595-3606 (1992), and Pearce et al., J. Med. Chem. 37, 526-541 (1994). As in the case of Schudel et al., none of these reported processes lead to the natural d-form of the tocotrienols, but rather produces racemic mixtures.

Several syntheses of natural form d-tocotrienols have been published. J. Scott et al., Helv. Chim. Acta 59, 290-306 (1976), started with trimethyl-hydroquinone and used a conventional optical resolution to provide the key intermediate 2,5,7,8-tetramethyl-6-hydroxychroman-2-acetic acid in the natural enantiomeric form. This compound was then elaborated into d-alpha-tocotrienol by a thrice-iterated process of adding 5-carbon sections of the side chain at a time, as follows:

Unfortunately this synthesis produced d-alpha-tocotrienol contaminated with about 20% of the isomeric compound shown. The authors were unable to separate pure natural-form tocotrienol from this mixture.

Sato et al. (Japanese Patent 63063674 A2 19880322 Showa; CAN 110:193145) described an approach to d-alpha-tocotrienol in which the diterpene alcohol geranylgeraniol is converted to an epoxytriene through Sharpless asymmetric epoxidation. The epoxidation is elaborated through several steps into the chiral acetoxy sulfide shown below. This C₂₀ chain is then attached to a suitably protected trimethylhydroquinone to provide the illustrated open-chain sulfide. The sulfide was subsequently desulfurized, the acetates removed, and cyclized to form a chiral chroman, as shown:

While the above synthesis produces natural-equivalent d-alpha-tocotrienol, it suffers from the fact that the geranylgeraniol starting material is very difficult to obtain.

In an apparent effort to overcome this difficulty, Sato et al. (JP 01233278 A2 19890919 Heisei, 1989; CAN 112:139621) report a second synthesis of d-alpha-tocotrienol which replaces the use of geranylgeraniol with a much more readily available side-chain synthon, the p-tolylsulfone derived from the readily available Clo terpene alcohol, geraniol. This synthesis, outlined below, requires an unsuitably large number of steps for commercial use.

In other relevant syntheses, Scott et al. prepared a chiral C₁₅ chroman and added 5-carbon chains to it three times to make the final product tocotrienol. Sato used a C₉ hydroquinone and a C₂₀ chain derived from geranylgeraniol. Sato used an intermediate C₁₈ chroman section and a Clo geranyl section.

In the only reported synthesis in the tocotrienol area that is truly highly convergent, Chenevert and Courchesne (Tetrahedron Letters 43, 7971-7973 (2002)) formed unnatural (S) or (i)-alpha-tocotrienol in a process-starting with the achiral triol, dl-chromantriol. As shown in the process illustrated below, Chenevert and Courchesne first converted the achiral triol to a (S) monoester via enzymatic desymmetrization and acetylation. Then, the (S) monoester was further treated with two equivalents of mesyl chloride to provide a (R) dimesylated monoester chroman. Reduction of the dimesylated monoester chroman produced (R)-chromanol, a chroman substituted with a hydroxymethyl group at the 2-position and a hydroxyl group at the 6-position of the chroman ring, and having (R) absolute configuration at the chiral 2-position carbon. Unnatural (S) or (l)-alpha-tocotrienol was thereafter produced from the 14-carbon (R)-chromanol compound via substituting the hydroxyl group at the 6-position with a benzyl ester protecting group, substituting the hydroxyl portion of the 2-hydroxymethyl group with a triflate (—OSO₂CF₃) leaving group to form a triflated chroman protected at the 6-position. The triflated chroman was thereafter coupled with phenyl farnesyl sulfone, i.e., a 15-carbon branched carbon chain having three methylated trans double bond sites corresponding to the 16-carbon side chain of a tocopherol, less the methyl carbon attached to the 2-position carbon of the chroman ring. As generation of the carbanion from the sulfone allowed for farnesyl group alkyl substitution of the triflate leaving group on the chroman ring, alpha-tocotrienol retaining the unnatural (S) or (l) configuration at the chiral chroman carbon is produced. The process is illustrated below:

The use of the achiral chroman triol as starting material in the (I)-alpha-tocotrienol synthesis of Chenevert and Courchesne does not show any advantages in either yield, number of steps, or economic advantage over previously reported chemistry that has suffered from being unattractive in each of these aspects. Moreover, the tocotrienol produced thereby is in the unnatural, and far less useful, (l) enantiomeric form.

In light of the above, there remains a need for commercially suitable processes of synthesizing members of the naturally occurring d-tocotrienol family using commercially available starting materials and requiring a number of steps that is economically feasible on a commercial scale. New routes for producing heretofore relatively unavailable starting materials for such synthesis would be valuable. In particular, there is a need for a more economically acceptable starting materials and syntheses for making each of d-alpha, d-beta, d-gamma, and d-delta tocotrienols.

BRIEF SUMMARY OF THE INVENTION

The present invention is a process of forming a natural form d-tocotrienol from a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the formula shown by (I), in single enantiomer form,

wherein R₁ is —H or —CH₃, R₂ is —H or —CH₃, and R₃ is —CH₃.

Compound (I) is converted to a (2S) protected chroman sulfonate having the formula as shown by (II), wherein P is a protecting group and Q is a sulfone leaving group.

Q is then displaced with a farnesyl group via a Grignard reaction to provide a compound of formula (III).

P is replaced with a hydrogen atom via hydrolysis to form the respective beta-, gamma-, or delta-d-tocotrienol product.

In another aspect of the present invention, a natural form d-tocotrienol is made from converting the (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) to a protected chroman sulfonate having the structure and absolute configuration of (S) as shown by formula (XIII). Thereafter, compound (XIII)

is reacted with a farnesyl carbanion to form a protected sulfonyl-substituted tocotrienol. Thereafter, the aryl sulfonyl group and protecting group are replaced with a hydrogen atom via reduction to form a d-tocotrienol product of formula (IV),

The invention further includes several methods for providing the chroman diol compound of formula (I).

DETAILED DESCRIPTION

In accordance with the objectives stated above, the present invention, in one aspect, is a novel process for preparing d-beta-, d-gamma-, and d-delta-tocotrienol. The present process is improved over existing processes in that it is a highly convergent synthesis using more readily available starting materials. For convenience sake, the process is hereinafter described with specific reference to formation of d-beta-tocotrienol, but is equally applicable to formation of the d-gamma-, and d-delta-tocotrienol, unless stated otherwise.

The present invention provides a process for preparing tocotrienol compounds, which are in all respects identical to the tocotrienols obtained from natural sources, through attachment of a suitably substituted 15-carbon farnesyl chain to a single-enantiomer chroman derivative suitably substituted for carbon-carbon bond formation with the aforementioned farnesyl derivative. In the present process of forming the d-beta-tocotrienol, a single enantiomer (2S)-chromanol (diol) is coupled with a substituted farnesyl group, a 15-carbon chain having three methylated trans double bond sites corresponding to the side chain of the tocotrienol compound. Highly convergent coupling between a (2S) chroman-based compound and a farnesyl anion is accomplished in the present invention in a first synthesis wherein a (2S)-chromanol derivative is reacted with a farnesyl Grignard reagent, and in an alternative synthesis wherein the above referenced chemistry disclosed by Chenevert and Courchesne is applied to a (2S)-chromanol instead of a (2R)-chromanol. Still further, the present invention includes new and improved avenues for providing the single enantiomer (2S)-chromanol compound for use in combination with either of the two tocotrienol syntheses. As used herein, a tocotrienol product containing greater than 90% of either the R or S enantiomer, and preferably greater than 95% of the particular enantiomer, is considered to be in the “single enantiomer” form.

The present invention includes a process of forming d-beta-tocotrienol from a (2S) chromanol comprising providing a single enantiomer (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman (the “(2S) chromanol”), as shown below in structure (1).

The process further continues by protecting the C-6 chroman position via selectively converting the C-6 hydroxyl group to an ester or ether. Thereafter, the chroman derivative is sulfonated at the intended farnesyl chain attachment site via substituting the hydroxyl portion of the C-2 hydroxymethyl group with a sulfonate anion (OSO₂R), represented below in structure (2) by Q.

The protected chroman sulfonate is then reacted with a Grignard reagent prepared from a farnesyl halide, said Grignard reagent having the structure (3) below wherein X is iodine, bromine, or chlorine:

The Grignard reaction is conducted under the influence of a lithium cuprate catalyst such as Li₂CuCl₄ to produce a protected d-beta-tocotrienol, from which natural-equivalent d-beta-tocotrienol is obtained after deprotection. In the above step of selectively substituting the C-6 hydroxyl group with an ester or ester protecting group P, a suitable protecting group is one which resists reaction during the subsequent steps of sulfonation and Grignard reaction. Examples of especially suitable protecting groups include p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, and silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl ethers. The most preferred protecting group in the present invention is p-toluenesulfonate.

Methods for conducting the protecting and deprotecting steps are widely known in the art. For a discussion of the application and removal of protecting groups specifically for phenols, see T. Greene and P. Wuts, “Protecting Groups in Organic Synthesis, 3rd ed., Wiley, NY, 1999, pp. 249-287, incorporated herein by reference.

In the above step of sulfonating the C-2 hydroxyalkyl group, a suitable sulfonate anion is one that performs as a very good leaving group in the subsequent copper-catalysed reaction with the Grignard reagent. Examples of particularly suitable sulfonate anions for use in this step include the phenyl sulfonate, p-tolyl sulfonate, p-alkylphenyl sulfonate, and perfluoroalkyl sulfonate, with p-tolyl sulfonate (commonly known as tosylate), being preferred.

In the Grignard reaction step of the process, the protected sulfonate chroman is reacted with the magnesium farnesyl halide under the influence of a lithium cuprate catalyst chosen from the group comprising preferably Li₂CuCl₄, or alternatively Li₂CuBr₄, and Li₂CuI₄. Suitable solvents to be used as the medium for this reaction include those ether solvents which are practical for the preparation of Grignard reagents, such as diethyl ether, symmetrical and unsymmetrical dialkyl ethers bearing C₁-C₅ alkyl groups, and cyclic ethers such as tetrahydrofuran or 1,4-dioxane. The reaction may be run at temperatures ranging from about −78° C. to about 100° C. It is preferred that the reaction be run in tetrahydrofuran solvent between about −50° C. and about 0° C. The product of the Grignard reaction is the protected d-beta-tocotrienol derivative shown below as structure (4).

An enantiomerically pure d-beta-tocotrienol product is obtained from the protected tocotrienol derivative by a step of removing of the protecting group by methods well known in the literature. For instance, where the P is a p-toluenesulfonate ester group, the group may be removed via hydrolysis by treatment with 1 to 5 equivalents of potassium or sodium hydroxide in a solvent mixture comprising water and a C₁-C₅ alcohol in a ratio of between about 1:10 to about 10:1, at a temperature ranging from about 0° C. to about 150° C. The use of KOH in ethanol/water at reflux temperature is preferred to hydrolyze the protecting group P—O bond and leave a 6-position hydroxyl group.

In another aspect of the present invention referred to herein as route B, d-beta-tocotrienol is formed from the (2S) chromanol, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman. The (2S) chromanol is converted through the chemical operations of phenolic benzylation (or application of a protecting group other than the benzyl ether to the phenolic hydroxyl group) and triflation (i.e., formation of the triflate or trifluoromethanesulfonate ester), to a chroman triflate having the following structure:

The chroman triflate is thereafter reacted with the following farnesyl aryl sulfone carbanion,

thus forming the protected d-beta-tocotrienol substituted with an aryl sulfone at the 2′ sidechain position as shown below as structure (7):

The present route B process proceeds further by reductively removing the phenylsulfone group and the protecting group from the molecule using methods well known in the literature, to provide a d-beta-tocotrienol product. The aryl sulfone group is replaced by a hydrogen atom using known reducing reagents and conditions. An exemplary reducing method employs lithium metal dissolved in liquid ammonia or in methylamine or ethylamine at about −50° C. to about 25° C., or as taught by D. Eren and E. Keinan (J. Am. Chem. Soc. 110, 4356-4362 (1988)) using lithium triethylborohydride in tetrahydrofuran solvent containing a trace of a palladium catalyst such as Pd(dppp)Cl₂ (dppp=bis(diphenylphosphinylpropane) at temperatures between about −30° C. and about +30° C.

The farnesyl aryl sulfone carbanion used in route B is prepared through methods known in the art such as reacting farnesyl bromide or chloride with the sodium salt of p-toluenesulfinic acid in a solvent such as dimethylformamide or dimethylsulfoxide, or in a biphasic water-organic solvent mixture using a phase transfer catalyst. The aryl group attached to the sulfur in the molecule can be phenyl, (preferably) p-tolyl, or other p-alkylphenyl. Deprotenation of the farnesyl aryl sulfone to a carbanion is conducted using a strong, non-nucleophillic base such as n-butyllithium (preferably), phenyllithium, or a secondary or tertiary alkyllithium compound in a solvent such as tetrahydrofuran or a C₁-C₅ symmetrical or unsymmetrical dialkyl ether, either singly or admixed with hexamethylphosphoramide, at a temperature between −70° C. and +25° C. The carbanion, which is not isolated, is negatively charged at the carbon atom attached to the sulfur atom and thus reacts with the protected chroman sulfonate.

The (2S) chromanol of structure (1) for use as starting material in producing d-tocotrienol via the above two syntheses is not presently commercially available.

Thus, there is a need for improved methods of providing the (2S) chromanol starting material in order to attain maximum benefit from the tocotrienol syntheses of the present invention for the beta-, gamma-, and delta-tocotrienols. The present invention further includes three new methods for providing the single enantiomer chroman derivatives represented generally as formula (I) and shown specifically below as, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman (beta-series), (2S) 2-hydroxymethyl-6-hydroxy-2,7,8-trimethylchroman (gamma-series), and (2S) 2-hydroxymethyl-6-hydroxy-2,8-dimethylchroman (delta-series).

In the first method for forming the single enantiomer chroman derivative, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman for use as starting material in the present tocotrienol syntheses, the known compound methyl-2-methyl-4-hydroxybut-2-ene is reacted with 2,5-dimethylhydroquinone in the presence of a Lewis acid catalyst in a condensation reaction wherein the hydroxyl group is removed from the ester chain forming a cation which replaces the hydrogen atom at the C-3 ring position of the hydroquinone ring to provide an ester-substituted hydroquinone, as shown:

While the use of the methyl ester shown is preferred, it is understood that other esters such as the ethyl, propyl, butyl, benzyl, and the like may also be utilized. The preferred catalyst is boron trifluoride. The preferred solvent is tetrahydrofuran or a symmetrical or unsymmetrical dialkyl ether having no more than 8 carbon atoms. Other Lewis acids such as aluminum trichloride, ferric chloride, stannic chloride, and the like may be used instead of boron trifluoride. This reaction can also be conducted in a hydrocarbon solvent such as benzene, toluene, xylenes, and the like. It is also possible to carry out this reaction using a monoprotected version of the dimethylhydroquinone such as 2,5-dimethylhydroquinone monobenzoate, monotosylate, or methyl or benzyl ether.

The ester-substituted hydroquinone is then treated with a strong acid such as HCl, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid in a solvent such as a dialkyl ether or tetrahydrofuran, hydrocarbon such as toluene, benzene, or an ester solvent such as methyl, ethyl, or butyl acetate to provide a racemic chroman-2-carboxylic estser. This reaction is preferably carried out at a temperature of between 0 and 100 deg C. The racemic chroman-2-carboxylic ester product of this reaction is then isolated by conventional means and subjected to reduction of the ester group to the hydroxyl oxidation state.

The preferred reagent for carrying out this reduction is a hydride reagent such as lithium aluminum hydride, diisobutyl aluminum hydride, or sodium bis(2-methoxyethoxy)aluminum hydride. Other preferred reagents include diborane or the technique of catalytic hydrogenation using a catalyst such as rhodium on alumina, platinum on carbon, platinum on alumina, and the like, under a pressure of between about 20 to about 2000 psi of hydrogen. It is most preferred to use sodium bis(2-methoxyethoxy)aluminum hydride in toluene, tetrahydrofuran, or dialkyl ether solvents at temperatures between about −20 and about +50 deg C.

The resulting racemic chromanol compound is then subjected to kinetic resolution by reaction with succinic anhydride in the presence of a suitable lipase enzyme catalyst such as the preferred Amano PS-30 lipase, either in the powdered form provided by the manufacturer or supported on a suitable inert support such as Celite filter-aid, using an inert solvent such as tert-butyl methyl ether at temperatures between 0 and +40 deg C. This procedure is perfectly analogous to that taught by Hyatt and Skelton (Tetrahedron Asymmetry 8, 523-526 (1997)), and provides, after isolation of the succinate ester of the (S) enantiomer (which is in the same configuration as the natural (R) tocotrienols) and subsequent hydrolytic removal of the succinate ester group as taught by Hyatt and Skelton, the pure single-enantiomer (2S) chromanol having the structure and absolute configuration as the compound shown by formula (I).

In the second method for forming the single enantiomer chroman derivative, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman for use as starting material in the present tocotrienol syntheses, a suitably monoprotected 2,5-dimethylhydroquinone is reacted with the compound 3-hydroxy-3-methyl-1,4-pentadiene to produce 2-vinyl-2,5,8-trimethylchroman-6-ol:

In this second embodiment, the protecting group may be chosen from those phenolic hydroxylprotection groups known and discussed by Greene and Wuts as referenced above. Suitable examples include p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, and silyl ethers such as trimethylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl ethers, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate. It is most preferred that the protecting group is acetate or benzoate.

The acid catalyst for the condensation reaction may be a Lewis acid such as zinc chloride, boron trifluoride, or aluminum trichloride, or a Bronsted acid such as a mineral acid or trifluoroacetic acid, as taught by F. Ismail et al., Tetrahedron Letters 33, 3795-3796 (1992). It is preferred that the catalyst be trifluoroacetic acid, and the solvent be water. The reaction may be run between about −20 deg C. and +40 deg C.; it is preferred that it be done at about 20 deg C.

The oxidative cleavage of the vinyl group may be carried out using techniques well known in the art, such as the use of ozone, sodium dichromate, chromium trioxide, ruthenium tetrachloride and oxygen, or periodic acid/manganese dioxide. For a discussion of these reagents and typical reaction conditions, see J. March, “Advanced Organic Chemistry”, 4th ed., Wiley, New York, 1992, ppl 177-1182. In a most preferred embodiment the oxidation is accomplished by treatment with ozone, followed by zinc in acetic acid or by sodium borohydride, or by hydrogen gas at a pressure of between 15 and 50 PSI in the presence of a palladium or platinum or nickel catalyst such as 5% Pd on charcoal (preferred). In this embodiment the illustrated intermediate aldehyde is not produced, but the initially formed ozonide is reduced directly to the desired racemic chroman alcohol. The remaining protecting group my then be removed by treatment with appropriate reagents as taught by Greene and Wuts, such as sodium or potassium hydroxide, potassium carbonate, and the like, to produce an unprotected chroman alcohol which may be converted to the necessary single-enantiomer alcohol by the process technology of Hyatt and Skelton, as discussed in a previous embodiment.

In the third method for forming the single enantiomer chroman derivative, (2S) 2-hydroxymethyl-6-hydroxy-2,5,8-trimethylchroman for use as starting material in the present tocotrienol syntheses 2,5-dimethylhydroquinone is suitably protected using one of the above listed protecting group, preferably chosen from benzyl ether, acetate, benzoate, p-toluenesulfonate, and tetrahydropyranyl ether, and then brominated in a position ortho to the remaining phenolic hydroxyl group to form a protected bromodimethylhydroquinone. It is most preferred that the protecting group is acetate or benzoate. The protecting step may be conducted either before or after the bromination step. In a most preferred embodiment the protecting group is the benzyl ether, and the bromination is accomplished using N-bromosuccinimide and a catalytic amount of a C₁-C₁₀ trialkylamine, preferably a highly sterically hindered amine such as diisopropylethylamine.

Reaction of the protected bromodimethylhydroquinone with isoprene oxide is then carried out under catalysis with a suitable palladium catalyst such as Pd(Ph₃P)₄, Pd₂(dba)₃/R₃P (where dba=dibenzylideneacetone, and R=phenyl, o-tolyl, or alkyl having from 1 to 8 carbon atoms), or other homogeneous Pd⁰ catalyst. The use of such catalysts is discussed in detail by L. Hegedus, “Transition Metals in the Synthesis of Complex Organic Molecules, University Science Books, Mill Valley, Calif., 1994, Chapt. 9. In a preferred embodiment the catalyst is tetrakis(triphenylphosphine)palladium, the solvent is an ether such as diethyl ether or tetrahydrofuran, an ester such as ethyl acetate, or an inert aliphatic or aromatic hydrocarbon solvent having from 5 to 18 carbon atoms. In a most preferred embodiment the solvent is tetrahydrofuran and the temperature is about 10 to about 30 deg C.

The resulting compound, with or without the addition of an additional protecting group to the primary alcohol functional group (if it is desired to use a protecting group, the most preferred group is the benzyl ether), is subjected to a palladium-catalysed cyclization reaction (Heck reaction) using as catalyst Pd(OAc)₂ in the presence of a C₁-C₈ phosphine such as triphenylphosphine, tri(o-tolyl)phosphine, tributylphosphine, and the like. The solvent is chosen from the group comprising dimethylformamide, dimethyl acetamide, N-methylpyrollidone, and acetonitrile. In a preferred embodiment the phosphine is triphenylphosphine and the solvent is dimethylformamide. The reaction is carried out at a temperature between 0 deg C. and 150 deg C. The preferred range is between 30 and 100 deg C. and most preferably between 50 and 85 deg C. The product of this reaction is a protected chromene as shown in the above scheme.

The unwanted 3,4-olefinic linkage of the protected chromene is next reduced using catalytic hydrogenation, a well-known process in the art. The reaction is carried out in an inert solvent such as a C₁-C₈ alcohol, and ester such as methyl acetate or ethyl acetate, or an ether solvent having from 2 to 8 carbon atoms. The catalyst is chosen from the group comprising palladium on an inert support and platinum on an inert support. In a preferred embodiment the solvent is ethyl alcohol and the catalyst is 5% Pd on charcoal. Hydrogen is supplied to the reaction at a pressure of between 15 and 250 psi, preferably between 30 and 60 psi, and at a temperature about 0 deg C. and about 50 deg C. Under conditions of catalytic hydrogenation, the benzylic protecting groups are removed and the 3,4-double bonds are reduced. The resulting racemic chroman alcohol is then converted to the necessary single enantiomer chroman as described in a previous embodiment.

It should be noted that an existing method of producing the racemic chromanol is taught by Fukumoto et al in U.S. Pat. No. 5,495,026, and incorporated herein in its entirety. Fukumoto et al disclose a process for producing chromans which comprises reacting a phenol, a formaldehyde and an unsaturated compound having carbon-carbon double bond in the presence of a secondary amine and an acid at a temperature between about 100° C. to about 200° C. to produce a chroman, as shown below:

This invention is further illustrated by the following example of a preferred embodiment thereof. This example is included merely for purposes of illustration and is not intended to limit the scope of the invention.

EXAMPLES Example 1 Preparation of d-beta-tocotrienol Via Path A of the Present Invention

Step 1) Preparation of the ditoluenesulfonate of (S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol. A solution of 0.005 mole of (S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol in 20 ml of anhydrous pyridine was cooled to 0-5 deg C. under nitrogen and treated with 0.011 mole ofp-toluenesulfonyl chloride. The mixture was allowed to warm to room temperature overnight, and poured into 150 mL of ice water. The resulting mixture was extracted with ethyl acetate (3×50 ml) and the combined organic phase was washed with 5% aq. HCl, water and NaCl brine. The washed ethyl acetate phase was then dried with magnesium sulfate and stripped of solvent in vacuo to afford 0.0048 mole of ditoluenesulfonate of (S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol as a white solid.

Step 2) Preparation of d-beta-Tocotrienol. A solution of farnesyl bromide (0.005 mole) in anhydrous tetrahydrofuran was stirred at zero degrees under a nitrogen atmosphere. An amount of 0.005 mole of magnesium turnings and a small crystal of iodine was added thereto. The mixture was allowed to warm to room temperature to initiate the reaction. Completion of the reaction was evidenced by consumption of the magnesium metal. Thereafter, the resulting solution of farnesyl magnesium bromide (Grignard reagent) was cooled to 0-5 degrees and 2.5 mole % (1.25 ml) of a 0.10 molar solution of lithium tetrachlorocuprate in THF was added, followed by a solution of the ditoluenesulfonate prepared in stage 1) above in anhydrous THF. The mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was drowned in 150 ml of 0.1% aq. HCl and extracted with ethyl acetate. The extract was washed with water and brine, dried, and stripped of solvent. A 72% yield of d-beta-tocotrienol was provided after purification to a single enantiomer form.

Example 2 Preparation of d-beta-tocotrienol Via Route B of the Present Invention

Step 1) Preparation of racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol. Methyl-2,5,8-trimethyl-6-benzoyloxychroman-2-carboxylate was prepared (80% yield) from 2,3-dimethylhydroquinone monobenzoate, methyl methacrylate, and paraformaldehyde in the presence of acetic acid and dibutylamine, following the protocol of E. Fukumoto, M. Torihara, and Y. Tamai, U.S. Pat. No. 5,495,026. This ester was reduced using lithium aluminum hydride in tetrahydrofuran to provide racemic 2,5,8-triemthyl-6-hydroxychroman-2-methanol in 90-95% yield.

Step 2) Resolution of racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol. Following the protocol of J. Hyatt and C. Skelton (same ref as earlier in patent), reaction of the above alcohol with succinic anhydride in the presence of Amano PS-30 lipase supported on filter-aid gave an equimolar mixture of (2R)-2,5,8-trimethyl-6-hydroxychroman-2-methanol and the hemisuccinate ester of (2S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol. The latter compound was separated by acid/base workup, recrystallized, and de-succinoylated with methanolic sodium methoxide to give the desired (2S)-2,5,8-trimethyl-6-hydroxychroman-2-methanol in 96.6 enantiomeric excess.

Step 3) Preparation of (2S)-2,5,8-trimethyl-6-benzyloxychroman-2methanol trifluoromethanesulfonate: The above (2S)-alcohol was allowed to react with benzyl bromide in dimethylformamide in the presence of potassium carbonate at room temperature overnight to provide an 86% yield of the 6-benzyloxy derivative. This substance was allowed to react with trifluoromethanesulfonic anhydride in dichloromethane/triethylamine at low temperature to provide the title compound in 85% yield.

Step 4) Preparation of d-beta-Tocotriene. Phenyl 3,7,11-trimethyldodeca-2,6,10-trienyl sulfone was prepared by known methods from trans-farnesol, via farnesyl bromide which was reacted with sodium benzenesulfinate in dimethylformamide. A solution of this sulfone in anhydrous tetrahydrofuran was cooled to below −20 deg C. and treated with a solution of 1.1 molar equivalent of n-butyllithium in tetrahydrofuran. This was followed by addition of a solution of the trifluoromethanesulfonate from Step 3 in tetrahydrofuran. The mixture was allowed to warm to 0 deg C. and worked up by the usual methods known in the art. The yield of 3′-phenylsulfonyl-d-beta-tocotriene was 71%. This compound was subjected to removal of the phenyl sulfone group by reduction with 1 molar lithiumtriethyl borohydride/tetrahydrofuran in the presence of a catalytic amount of palladium bis[1,3-bis(diphenylphosphinoopropane] (“Pd(dppp)”) to afford d-beta-tocotrienol in 84% yield after purification.

The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention. 

1. A process of forming a d-tocotrienol comprising: a) providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the formula shown by (I), in single enantiomer form;

b) converting said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of (I) to a (2S) protected chroman sulfonate shown by formula (II);

c) displacing Q in said (2S) protected chroman sulfonate (II) by reacting said (2S) protected chroman sulfonate (II) with a farnesyl-magnesium halide in the presence of a lithium cuprate catalyst in an eiher solvent at a temperature between about −78° C. to about 100° C. to form a protected d-tocotrienol of formula (III); and

d) replacing P with a hydrogen atom in said protected d-tocotrienol of (III) via hydrolysis to form a d-tocotrienol product of formula (IV),

wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, except that R₁ and R₂ are not both methyl groups, and R₃ is a methyl group, further P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, still further wherein Q is selected from the group of sulfonate anions consisting of phenyl sulfonate, p-tolyl sulfonate, p-alkylphenyl sulfonate, and perfluoroalkyl sulfonate, and trialkylsilyl ethers having straight chain or branched alkyl chains having between 1 to 6 carbons.
 2. The process according to claim 1 wherein said d-tocotrienol product produced is in greater than 90.0 percent of the (R) enantiomeric form.
 4. The process according to claim 1 wherein P is ap-toluenesulfonyl group and Q is ap-toluenesulfonyl group.
 5. The process according to claim 1 wherein said lithium cuprate catalyst is chosen from the group of compounds consisting of Li₂CuCl₄, Li₂CuBr₄, and Li₂CuI₄.
 6. The process according to claim 1 wherein said d-tocotrienol product formed is d-alpha-tocotrienol, wherein each of R₁, R₂, and R₃ is a methyl group.
 7. The process according to claim 1 wherein said d-tocotrienol product formed is d-beta-tocotrienol, wherein each of R₁ and R₃ is a methyl group and R₂ is a hydrogen atom.
 8. The process according to claim 1 wherein said d-tocotrienol product formed is d-gamma-tocotrienol, wherein R₁ is a hydrogen atom and each of R₂ and R₃ is a methyl group.
 9. The process according to claim 1 wherein said d-tocotrienol product formed is d-delta-tocotrienol, wherein each of R₁ and R₂ is a hydrogen atom and R₃ is a methyl group.
 10. The process according to claim 1 wherein said step of providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure shown by (I), in single enantiomer form is conducted by a method comprising the steps of a) providing methyl-2-methyl-4-hydroxy-2-butenoate; b) reacting said methyl-2-methyl-4-hydroxy-2-butenoate with 2,5-dimethylhydroquinone under the influence of Lewis acid catalysis to provide the substituted hydroquinone having the structure of formula (V);

c) cyclizing said substituted hydroquinone of (V) under the influence of a protic or Bronsted acid to provide a racemic chroman ester having the structure of formula (VI);

d) reducing said racemic chroman ester of (VI) to its corresponding racemic chroman alcohol; and e) resolving said racemic chroman alcohol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound, wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group.
 11. The process according to claim 1 wherein said step of providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure shown by (I), in single enantiomer form is conducted by a method comprising the steps of a) reacting a protected 2,5-dimeihylhydroquinone with 3-methyl-3-hydroxy-1,4-pentadiene under the influence of a Bronsted acid to form a racemic 2-vinyl-2,5,8-trimethylchroman-6-ol having the structure of formula (VII);

b) oxidatively cleaving said vinylchroman compound of (VII) to form a chroman-2-aldehyde having the structure of formula (VIII);

c) reducing said chroman-2-aldehyde of (VIII) to its corresponding racemic chroman-2-alcohol; and (d) resolving said racemic chroman-2-alcohol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group.
 12. The process according to claim 1 wherein said step of providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I), in single enantiomer form is conducted by a method comprising the steps of a) reacting a protected 2,5-dimethyl-3-bromohydroquinone molecule having the structure of formula (IX) with isoprene oxide (1-methyl-1-vinyloxirane) under the influence of a palladium catalyst to provide an allylic ether compound having the structure of formula (X),

b) adding a protecting group to the primary hydroxyl group of said allylic ether compound of formula (X) to form a protected allylic ether compound having the structure of (XI);

c) cyclizing said protected allylic ether compound of (XI) using a Heck reaction to form a 3-chromene derivative having the structure of (XII);

d) hydrogenating said 3-chromene derivative of (XII) by way of catalytic hydrogenation to form a diprotected racemic 2,5,8-trimethylchroman-2-methanol; e) removing the protecting groups from said diprotected racemic 2,5,8-trimethylchroman-2-methanol to provide a racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol; and f) resolving said racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group.
 13. In a process of forming a d-beta-tocotrienol, d-gamma-tocotrienol or d-delta-tocotrienol from its corresponding (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure of formula (I),

the improvement comprising: providing said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of (I) by a) providing methyl-2-methyl-4-hydroxy-2-butenoate; b) reacting said methyl-2-methyl-4-hydroxy-2-butenoate with 2,5-dimethylhydroquinone under the influence of Lewis acid catalysis to provide the substituted hydroquinone having the structure of formula (V);

c) cyclizing said substituted hydroquinone of (V) under the influence of a protic or Bronsted acid to provide a racemic chroman ester having the structure of formula (VI),

d) reducing said racemic chroman ester of (VI) to its corresponding racemic chroman alcohol; and e) resolving said racemic chroman alcohol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound, wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group.
 14. In a process of forming a d-beta-tocotrienol, d-gamma-tocotrienol or d-delta-tocotrienol from its corresponding (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure of formula (I),

the improvement comprising: providing said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) by a) reacting a protected 2,5-dimethylhydroquinone with 3-methyl-3-hydroxy-1,4-pentadiene under the influence of a Bronsted acid to form a racemic 2-vinyl-2,5,8-trimethylchroman-6-ol having the structure of formula (VII);

b) oxidatively cleaving said vinylchroman compound of (VII) to form a chroman-2-aldehyde having the structure of formula (VIII);

c) reducing said chroman-2-aldehyde of (VIII) to its corresponding racemic chroman-2-alcohol; and d) resolving said racemic chroman-2-alcohol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group.
 15. In a process of forming a d-beta-tocotrienol, d-gamma-tocotrienol or d-delta-tocotrienol from its corresponding (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure shown by (I),

the improvement comprising providing said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) by a) reacting a protected 2,5-dimethyl-3-bromohydroquinone molecule having the structure of formula (IX) with isoprene oxide (1-methyl-1-vinyloxirane) under the influence of a palladium catalyst to provide an allylic ether compound having the structure of formula (X);

b) adding a protecting group to the primary hydroxyl group of said allylic ether compound of formula (X) to form a protected allylic ether compound having the structure of (XI);

c) cyclizing said protected allylic ether compound of (XI) using a Heck reaction to form a 3-chromene derivative having the structure of (XII);

d) hydrogenating said 3-chromene derivative of (XII) by way of catalytic hydrogenation to form a diprotected racemic 2,5,8-trimethylchroman-2-methanol; e) removing the protecting groups from said diprotected racemic 2,5,8-trimethylchroman-2-methanol to provide a racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol; and f) resolving said racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group.
 16. A process for forming d-tocotrienol, said process comprising: a) reacting a protected 2,5-dimethylhydroquinone with 3-methyl-3-hydroxy-1,4-pentadiene under the influence of a Bronsted acid to form a racemic 2-vinyl-2,5,8-trimethylchroman-6-ol having the structure of formula (VII);

b) oxidatively cleaving said vinylchroman compound of (VII) to form a chroman-2-aldehyde having the structure of formula (VIII);

c) reducing said chroman-2-aldehyde of (VIII) to its corresponding racemic chroman-2-alcohol; and d) resolving said racemic chroman-2-alcohol to form said 2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I); e) converting said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) to a protected chroman sulfonate having the structure and absolute configuration of (S) as shown by formula (XIII);

f) providing a farnesyl carbanion by deprotenating a farnesyl aryl sulfone; g) contacting said farnesyl carbanion with said protected chroman compound (XIII) in an ether solvent having from 1 to 5 carbons at a temperature of between about −70° C. to about +25° C. to form a protected sulfonyl-substituted tocotrienol having the structure and absolute configuration of formula (XIV); and

h) replacing the aryl sulfonyl group and P with a hydrogen atom via reduction to form a d-tocotrienol product of formula (IV), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group. still further wherein Ar is a phenyl group or ap-alkylphenyl group, and even still further wherein Tf is a sulfonate anion having a perfluoroalkyl chain of from 1 to 6 carbon atoms.
 17. A process for forming d-tocotrienol, said process comprising: a) reacting a protected 2,5-dimethyl-3-bromohydroquinone molecule having the structure of formula (IX) with isoprene oxide (1-methyl-1-vinyloxirane) under the influence of a palladium catalyst to provide an allylic ether compound having the structure of formula (X);

b) adding a protecting group to the primary hydroxyl group of said allylic ether compound of formula (X) to form a protected allylic ether compound having the structure of (XI);

c) cyclizing said protected allylic ether compound of (XI) using a Heck reaction to form a 3-chromene derivative having the structure of (MI);

d) hydrogenating said 3-chromene derivative of (XII) by way of catalytic hydrogenation to form a diprotected racemic 2,5,8-trimethylchroman-2-methanol; e) removing the protecting groups from said diprotected racemic 2,5,8-trimethylchroman-2-methanol to provide a racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol; f) resolving said racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I); g) converting said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) to a protected chroman sulfonate having the structure and absolute configuration of (S) as shown by formula (XIII);

h) providing a farnesyl carbanion by deprotenating a farnesyl aryl sulfone; i) contacting said farnesyl carbanion with said protected chroman compound (XIII) in an ether solvent having from 1 to 5 carbons at a temperature of between about −70° C. to about +25° C. to form a protected sulfonyl-substituted tocotrienol having the structure and absolute configuration of formula (XIV); and

j) replacing the aryl sulfonyl group and P with a hydrogen atom via reduction to form a d-tocotrienol product of formula (IV), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, 2-tetrahydrofuranyl ether, methoxymethyl ether, methoxyethoxymethyl ether, trimethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, acetate, benzoate, p-toluenesulfonate, methanesulfonate, and benzenesulfonate, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group. still further wherein Ar is a phenyl group or ap-alkylphenyl group, and even still further wherein Tf is a sulfonate anion having a perfluoroalkyl chain of from 1 to 6 carbon atoms.
 18. A process of forming a d-tocotrienol comprising: a) reacting a protected 2,5-dimethyl-3-bromohydroquinone molecule having the structure of formula (IX) with isoprene oxide (1-methyl-1-vinyloxirane) under the influence of a palladium catalyst to provide an allylic ether compound having the structure of formula (X);

b) adding a protecting group to the primary hydroxyl group of said allylic ether compound of formula (X) to form a protected allylic ether compound having the structure of (M);

c) cyclizing said protected allylic ether compound of (XI) using a Heck reaction to form a 3-chromene derivative having the structure of (XII);

d) hydrogenating said 3-chromene derivative of (XII) by way of catalytic hydrogenation to form a diprotected racemic 2,5,8-trimethylchroman-2-methanol; e) removing the protecting groups from said diprotected racemic 2,5,8-trimethylchroman-2-methanol to provide a racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol; f) resolving said racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I), g) converting said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (I) to a protected chroman sulfonate having the structure and absolute configuration of (S) as shown by formula (XIII);

h) providing a farnesyl carbanion by deprotenating a farnesyl aryl sulfone; i) contacting said farnesyl carbanion with said protected chroman compound (XIII) in an ether solvent having from 1 to 5 carbons at a temperature of between about −70° C. to about +25° C. to form a protected sulfonyl-substituted tocotrienol having the structure and absolute configuration of formula (MV); and

j) replacing the aryl sulfonyl group and P with a hydrogen atom via reduction to form a d-tocotrienol product of formula (IV), wherein P is a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, further wherein R₁ is a hydrogen atom or methyl group, R₂ is a hydrogen atom or methyl group, and R₃ is a methyl group, still further wherein Ar is a phenyl group or ap-alkylphenyl group, and even still further wherein Tf is a sulfonate anion having a perfluoroalkyl chain of from 1 to 6 carbon atoms. 